One study showed that TLR9 proteolysis is a multistep process with the initial cleavage that can be mediated by AEP or multiple members of the cathepsin family. The second event is mediated exclusively by cathepsins. TLR7 and TLR3 were reported to be cleaved in a similar manner (Ewald SE et al 2011). Cleavage of TLR3 is not shown in this reaction, since other studies demonstrated that the N-terminal region of TLR3 ectodomain was implicated in ligand binding, suggesting that TLR3 may function as a full-length receptor (Liu L et al 2008, Tokisue T et al 2008).
Both full-length receptor and cleaved fragment corresponding to the C-terminal part of TLR9 were capable to bind ligand, however only the processed form (TLR9 C-ter, aa 471-1032) was shown to bind MyD88 and induce signaling in different mouse cells (Ewald SE et al 2008).",
"cellular_location": "endolysosome membrane",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"P07858-1",
"P07711-1",
"P43235-1",
"P25774-1",
"Q99538-1"
],
"evidence": [
{
"id": "R-HSA-1678920",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-1678920"
}
]
},
{
"id": "R-HSA-1678981",
"name": "TLR9 processing at neutral pH",
"equation": "",
"summary": "TLR9 traffics to an endosomal vesicle where it is processed by cathepsin S at neural pH to generate an N-terminal product (TLR9 N-ter, aa 1-723). The N-terminal fragment of TLR9 also binds ligand, but in contrast to the C-terminal fragment it inhibits TLR9 signaling. Thus, a proper balance between the two proteolytic events probably regulates TLR9-mediated host responses. (Chockalingam A et al 2011).",
"cellular_location": "endolysosome membrane",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"P07711-1",
"O60911-1",
"P25774-1"
],
"evidence": [
{
"id": "R-HSA-1678981",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-1678981"
}
]
},
{
"id": "R-HSA-2130349",
"name": "Generation of CLIP from lip10",
"equation": "",
"summary": "The lip10 fragments bound in the nonameric complex are processed leaving only the CLIP fragment (81-105) bound to the MHC II peptide binding groove. Three cysteine proteases have been shown to be capable of digesting lip10, each with a different expression pattern among different APC. Cathepsin (Cat) S digests Ii in B cells and dendritic cells, thymic epithelial cells use Cat L and Cat L, while Cat S and F are active in macrophages (Villadangos, 2001; Bryant et al, 2002). Cat S appears to be the major enzyme involved as demonstrated by the use of specific inhibitors and of knockout experiments (Stumptner-Cuvelette et al. 2002). Following lip10 digestion, the MHC-like molecule HLA-DM induces the exchange of CLIP fragment for a highly diverse array of antigens (Denzin & Cresswell. 1995).",
"cellular_location": "lysosomal membrane, lysosomal lumen",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"Q9UBX1-1",
"P10619-1",
"P07339-1",
"P07858-1",
"P07711-1",
"P14091-1",
"P43234-1",
"P53634-1",
"P43235-1",
"O60911-1",
"P25774-1"
],
"evidence": [
{
"id": "R-HSA-2130349",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-2130349"
}
]
},
{
"id": "R-HSA-2130504",
"name": "Cleavage of lip22 to lip10",
"equation": "",
"summary": "The cleavage of lip22 occurs in residues 115-125, closer to the C-terminus than CLIP (residues 81-105). The resulting lip10 fragment is approximately 100 residues long and extends just through the C-terminus of the Ii CLIP. The proteases responsible for generating lip10 in vivo are not determined. Cysteine proteases like cathepsin S (CatS) are capable of degrading lip22 to lip10 (Bania et al. 2003) but in the presence of LHVS, an inhibitor of CatS, lip22 degradation is still observed, suggesting that other proteases are involved (Villadangos et al. 1997), possibly aspartic proteinases such as cathepsins D and E (Kageyama et al. 1996). The degradation of lip22 may depend on cell type (Bania et al. 2003). The lip22 and lip10 intermediate forms are still maintained as a nonameric complex due to the existence of the last trimerisation domain in the transmembrane region.",
"cellular_location": "lysosomal membrane, lysosomal lumen",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"Q9UBX1-1",
"P10619-1",
"P07339-1",
"P07858-1",
"P07711-1",
"P14091-1",
"P43234-1",
"P53634-1",
"P43235-1",
"O60911-1",
"P25774-1"
],
"evidence": [
{
"id": "R-HSA-2130504",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-2130504"
}
]
},
{
"id": "R-HSA-2130706",
"name": "MHC class II antigen processing",
"equation": "",
"summary": "Antigen processing and loading on to MHC class II molecules occurs in late endocytic/lysosomal vesicles, where epitopes which require extensive proteolytic processing are generated (Bryant & Ploegh 2003). These late endosome/lysosomal-like compartments are enriched in MHC II and are referred to as MIICs (MHC class II compartments) (Peters et al. 1991). A variety of lysosomal proteases like cathepsins S, D, B etc. and Asparaginyl endopeptidase (AEP) are suggested to be involved in the processing of antigens to generate CD4+ T cell epitopes (Deusing et al. 1998, Shi et al. 1999, Pluger et al. 2002, Watts et al. 2005). An initial cleavage by endopeptidases (AEP) would be necessary to unlock the antigen and allow further trimming of the ends by exopeptidases (Cathepsins). In the acidic environment of the lysosome, cathepsins are generally activated by autocatalytic cleavage of a propeptide which otherwise blocks the active site.",
"cellular_location": "lysosomal lumen",
"input_participant_list": [],
"output_participant_list": [
"R-ALL-2213226"
],
"enzyme_list": [
"Q9UBX1-1",
"P10619-1",
"P07339-1",
"P07858-1",
"P07711-1",
"P14091-1",
"P43234-1",
"P53634-1",
"P43235-1",
"O60911-1",
"P25774-1"
],
"evidence": [
{
"id": "R-HSA-2130706",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-2130706"
}
]
},
{
"id": "R-HSA-2168923",
"name": "Collagen type XVIII endostatin release",
"equation": "",
"summary": "Collagen type XVIII is a heparan sulfate proteoglycan associated with the basement membranes of almost all epithelia and endothelia. It has a large C-terminal noncollagenous domain. Mouse knockouts suggest that it may have a role in maintaining the structural integrity of the extracellular matrix (Utriainen et al. 2004).
Proteolytic cleavage of the C-terminal noncollagenous domain by matrix metalloproteinases (Heljasvaara et al. 2005) releases 18 to 38 kDa C-terminal proteolytic fragments, collectively named endostatin. They have anti-angiogenic activity (O'Reilly et al. 1997, St\u00e4ndker et al. 1997) and suppress primary tumor and metastasis growth in experimental animal models (Ortega & Werb 2002). It is not clear whether this collagen subtype forms supramolecular assemblies (Myllyharju & Kivirikko, 2004) but thought likely, via a similar mechanism to the related collagen XV (Hurskainen et al. 2010).
Endostatin-like fragments are released from collagen type XVIII by MMP 7 (Lin et al. 2001), 3, 9, 12, 13 (Ferreras et al. 2000) and 20 (Heljasvaara et al. 2005). Several cathepsins and elastase can bring about endostatin release (Ferreras et al. 2000, Felbor et al. 2000).",
"cellular_location": "extracellular region",
"input_participant_list": [
"R-HSA-2172281"
],
"output_participant_list": [
"R-HSA-2470858"
],
"enzyme_list": [
"P39900-1",
"P07858-1",
"P07711-1",
"P14780-1",
"P43235-1",
"P45452-1",
"P09237-1",
"P08254-1",
"O60882-1"
],
"evidence": [
{
"id": "R-HSA-2168923",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-2168923"
}
]
},
{
"id": "R-HSA-2213200",
"name": "Release of endostatin-like peptides",
"equation": "",
"summary": "Collagens XV and XVIII are basement membrane associated collagens that can be cleaved to generate the antiangiogenic peptides restin (endostatin-XV) and endostatin (endostatin-XVIII), respectively (O'Reilly et al. 1997, Ramachandran et al. 1997, Sasaki et al. 2000). Endostatin fragments of differing molecular size (14-30 kDa) have been identified in vivo. Furthermore the C-terminal domains of several other collagens (IV, VIII, XIX) have anti-angiogenic and anti-tumoral activities (Ricard-Blum & Ballut 2011). Several proteases are able to generate endostatin from collagen XVIII including MMP-3, -7, -9, -13 and -20 and cathepsins B, V, S and L (Heljasvaara et al. 2005, Ma et al. 2007, Veillard et al. 2011). Endostatin inhibits proliferation of endothelial cells, angiogenesis and tumor growth in vivo (O'Reilly et al. 1997).",
"cellular_location": "extracellular region",
"input_participant_list": [
"R-HSA-2152295"
],
"output_participant_list": [
"R-HSA-2225571",
"R-HSA-2225572",
"R-HSA-2225575",
"R-HSA-2225576"
],
"enzyme_list": [
"P07858-1",
"P07711-1",
"P14780-1",
"O60911-1",
"P25774-1",
"P45452-1",
"P09237-1",
"P08254-1",
"O60882-1"
],
"evidence": [
{
"id": "R-HSA-2213200",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-2213200"
}
]
},
{
"id": "R-HSA-2471621",
"name": "Endostatin degradation by cathepsins",
"equation": "",
"summary": "As well as generating endostatin from collagen XVIII, cathepsins L and B quickly degrade it, as do cathepsins D and K. In contrast MMPs that produce endostatin do not cleave it further (Ferreras et al. 2000).",
"cellular_location": "extracellular region",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"P07339-1",
"P07858-1",
"P07711-1",
"P43235-1"
],
"evidence": [
{
"id": "R-HSA-2471621",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-2471621"
}
]
},
{
"id": "R-HSA-3814820",
"name": "HSPG2 (perlecan) is cleaved by BMP1, TLL1, TLL2, Cathepsin L1",
"equation": "",
"summary": "Endorepellin is the 85-kDa C-terminal domain V of HSPG2 (perlecan). It consists of a series of laminin-like globular (LG) domains interconnected by short epidermal growth factor-like repeats (Hohenester & Engel 2002). Endorepellin has angiostatic activity (Mongiat et al. 2003) which is primarily localised in the LG3 domain (Bix et al. 2004). ; ; Bone morphogenetic protein 1 (BMP1), its isoform mammalian Tolloid (mTLD), mammalian Tolloid-like-1 and -2 (TLL1, TLL2) (Gonzalez et al. 2005) and cathepsin-L1 (Cailhier et al. 2008) can liberate LG3 by cleaving endorepellin between Asn4196 and Asp4197.",
"cellular_location": "extracellular region",
"input_participant_list": [],
"output_participant_list": [
"R-HSA-3827968",
"R-HSA-3827980"
],
"enzyme_list": [
"P07711-1",
"O43897-1",
"P13497-1",
"Q9Y6L7-1"
],
"evidence": [
{
"id": "R-HSA-3814820",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-3814820"
}
]
},
{
"id": "R-HSA-8938108",
"name": "SERPINB13 binds cathepsin L",
"equation": "",
"summary": "SERPINB13 binds the lysosomal cystein protease cathepsin L and inhibits its catalytic activity (Jayakumar et al. 2003, Welss et al. 2003). It is uncertain whether SERPINB13 functions in the lysosomes or exclusively in the cytosol, where it would inhibit the enzymatic activity of ectopic cathepsin L (Welss et al. 2003).",
"cellular_location": "lysosomal lumen",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"P07711-1",
"O60911-1"
],
"evidence": [
{
"id": "R-HSA-8938108",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-8938108"
}
]
},
{
"id": "R-HSA-9685655",
"name": "CTSL bind CTSL inhibitors",
"equation": "",
"summary": "Lysosomes play critical roles in human biology receiving, trafficking, processing, and degrading biological molecules from cellular processes such as endocytosis, phagocytosis, autophagy and secretion. Lysosomes house around sixty proteolytic enzymes, among them cathepsins. Cathepsins are involved in many processes involving cell death, protein degradation, post-translational modifications of proteins, extracellular matrix (ECM) remodeling, autophagy, and immune signaling. The early stages of the viral life cycle involve the cleavage of the viral spike protein by cathepsin L (CTSL) in late endosomes, facilitating viral RNA release to continue viral replication. Teicoplanin, a glycopeptide antibiotic used to treat Gram-positive bacterial infection, especially in Staphylococcal infections, was shown to have efficacy in vitro against Ebola Virus, MERS and SARS-CoV-1 (Zhou et al. 2016).
Teicoplanin is thought to inhibit the low pH cleavage of the viral spike protein by CTSL in late endosomes thereby preventing the release of genomic viral RNA and the continuation of virus replication cycle (Baron et al. 2020). The target sequence that serve as the cleavage site for CTSL is conserved in the SARS-CoV-2 spike protein (Zhou et al. 2020 [preprint]). Further investigation is required to determine the therapeutic potential of teicoplanin in COVID-19 patients.
Relacatib is an investigational drug trialed for the treatment of osteoporosis (Duong et al. 2016). It is a potent CTSK inhibitor but also shows activity against CTSL (Kumar et al. 2007) so could potentially be investigated for Covid-19 patients. The antileprotic drug clofazimine and the antituberculous drugs rifampicin and isoniazid have been shown to inhibit cathepsins B, H and L from purified goat and bovine brains (Kamboj et al. 2003).",
"cellular_location": "endocytic vesicle lumen",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"P07711-1"
],
"evidence": [
{
"id": "R-HSA-9685655",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9685655"
}
]
},
{
"id": "R-HSA-9686710",
"name": "Cleavage of S protein into S1:S2",
"equation": "",
"summary": "Spike protein S1: attaches the virion to the cell membrane by interacting with host receptor, initiating the infection.
;
; Spike protein S2: Acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis.
;
; Spike protein S2: mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Under the current model, the protein has at least three conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes.
;
; Within the host cell endocytic vesicle, SARS-CoV-1 Spike (S) protein is cleaved between residues 797 and 798 by cathepsin L1 (CTSL) (Huang et al. 2006). The roles of S protein in viral binding to the host cell membrane and fusion of viral and host cell membranes and thus the central role of S protein in determining the host range and tissue tropisms of the virus are reviewed by Belouzard et al. (2012).",
"cellular_location": "endocytic vesicle lumen",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"Q9BYF1-1",
"P07711-1"
],
"evidence": [
{
"id": "R-HSA-9686710",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9686710"
}
]
},
{
"id": "R-HSA-9694287",
"name": "Cleavage of S protein into S1:S2",
"equation": "",
"summary": "Within the host cell endocytic vesicle, SARS-CoV-2 Spike (S) protein is cleaved, probably between residues 815 and 816 by cathepsin L1 (CTSL) (Zhao et al, 2021; Huang et al. 2006). The roles of S protein in viral binding to the host cell membrane and fusion of viral and host cell membranes and thus the central role of S protein in determining the host range and tissue tropisms of the virus are reviewed by Jackson et al, 2021, and Trbojevi\u0107-Akma\u010di\u0107 et al, 2021.; ; The CTSL/CTSB expression inhibitor amantadin is an approved generic drug with mild side effects used as a preventive agent for influenza and for Parkinson\u2019s disease. Amantadine inhibited CTSL enzyme activity in the setting of SARS-CoV-2 pseudovirus infection and significantly inhibited SARS-CoV-1 and SARS-CoV-2 cell entry with little cytotoxicity (Zhao et al, 2021). Several clinical studies with amantadine for COVID-19 treatment are in the recruiting stage (NCT04952519, NCT04894617, NCT04854759).",
"cellular_location": "endocytic vesicle lumen",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"Q9BYF1-1",
"P07711-1"
],
"evidence": [
{
"id": "R-HSA-9694287",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9694287"
}
]
}
],
"reaction_participants": [
{
"participant_id": "R-ALL-1236715",
"participant_name": "Exogenous soluble antigen [early endosome lumen]",
"crossref": [
{
"id": "16670",
"database": "ChEBI",
"url": ""
},
{
"id": "C00012",
"database": "COMPOUND",
"url": ""
}
]
},
{
"participant_id": "R-ALL-1236722",
"participant_name": "precursor peptide fragment (>16 aa) [early endosome lumen]",
"crossref": [
{
"id": "25676",
"database": "ChEBI",
"url": ""
},
{
"id": "25676",
"database": "ChEBI",
"url": ""
},
{
"id": "25676",
"database": "ChEBI",
"url": ""
},
{
"id": "25676",
"database": "ChEBI",
"url": ""
}
]
},
{
"participant_id": "R-ALL-2213226",
"participant_name": "MHC class II epitopes [lysosomal lumen]",
"crossref": [
{
"id": "15841",
"database": "ChEBI",
"url": ""
},
{
"id": "15841",
"database": "ChEBI",
"url": ""
},
{
"id": "15841",
"database": "ChEBI",
"url": ""
},
{
"id": "15841",
"database": "ChEBI",
"url": ""
},
{
"id": "15841",
"database": "ChEBI",
"url": ""
},
{
"id": "15841",
"database": "ChEBI",
"url": ""
}
]
},
{
"participant_id": "R-ALL-8943711",
"participant_name": "L-amino acid [early endosome lumen]",
"crossref": [
{
"id": "59869",
"database": "ChEBI",
"url": ""
},
{
"id": "59869",
"database": "ChEBI",
"url": ""
},
{
"id": "59869",
"database": "ChEBI",
"url": ""
},
{
"id": "59869",
"database": "ChEBI",
"url": ""
}
]
},
{
"participant_id": "R-HSA-2152295",
"participant_name": "Collagen type XVIII [extracellular region]",
"crossref": [
{
"id": "CPX-1759",
"database": "ComplexPortal",
"url": ""
}
]
},
{
"participant_id": "R-HSA-2172281",
"participant_name": "Collagen type XVIII multimer [extracellular region]",
"crossref": [
{
"id": "36080",
"database": "ChEBI",
"url": ""
}
]
},
{
"participant_id": "R-HSA-2225571",
"participant_name": "COL15A1(?-1211) [extracellular region]",
"crossref": [
{
"id": "ENST00000375001",
"database": "Ensembl",
"url": ""
},
{
"id": "ENSP00000364140",
"database": "Ensembl",
"url": ""
},
{
"id": "3N3F",
"database": "PDB",
"url": ""
},
{
"id": "P39059",
"database": "Pharos - Targets",
"url": ""
},
{
"id": "ENSG00000204291-COL15A1",
"database": "HPA",
"url": ""
},
{
"id": "P39059",
"database": "UniProt",
"url": ""
},
{
"id": "P39059",
"database": "PRO",
"url": ""
},
{
"id": "NP_001846.3",
"database": "RefSeq",
"url": ""
},
{
"id": "ENSG00000204291",
"database": "OpenTargets",
"url": ""
},
{
"id": "ENSG00000204291",
"database": "Ensembl",
"url": ""
},
{
"id": "P39059",
"database": "GeneCards",
"url": ""
},
{
"id": "XP_011516516.1",
"database": "RefSeq",
"url": ""
}
]
},
{
"participant_id": "R-HSA-2225572",
"participant_name": "COL15A1(1212-1388) [extracellular region]",
"crossref": [
{
"id": "ENSG00000204291",
"database": "Ensembl",
"url": ""
},
{
"id": "XP_011516516.1",
"database": "RefSeq",
"url": ""
},
{
"id": "P39059",
"database": "GeneCards",
"url": ""
},
{
"id": "P39059",
"database": "PRO",
"url": ""
},
{
"id": "NP_001846.3",
"database": "RefSeq",
"url": ""
},
{
"id": "ENSG00000204291",
"database": "OpenTargets",
"url": ""
},
{
"id": "ENSG00000204291-COL15A1",
"database": "HPA",
"url": ""
},
{
"id": "P39059",
"database": "Pharos - Targets",
"url": ""
},
{
"id": "3N3F",
"database": "PDB",
"url": ""
},
{
"id": "P39059",
"database": "UniProt",
"url": ""
},
{
"id": "ENST00000375001",
"database": "Ensembl",
"url": ""
},
{
"id": "ENSP00000364140",
"database": "Ensembl",
"url": ""
}
]
},
{
"participant_id": "R-HSA-2225575",
"participant_name": "COL18A1(1572-11754) [extracellular region]",
"crossref": [
{
"id": "ENSP00000498485",
"database": "Ensembl",
"url": ""
},
{
"id": "P39060",
"database": "PRO",
"url": ""
},
{
"id": "ENSG00000182871-COL18A1",
"database": "HPA",
"url": ""
},
{
"id": "ENST00000651438",
"database": "Ensembl",
"url": ""
},
{
"id": "NP_569711.2",
"database": "RefSeq",
"url": ""
},
{
"id": "3HSH",
"database": "PDB",
"url": ""
},
{
"id": "NP_569712.2",
"database": "RefSeq",
"url": ""
},
{
"id": "ENSG00000182871",
"database": "Ensembl",
"url": ""
},
{
"id": "3HON",
"database": "PDB",
"url": ""
},
{
"id": "P39060",
"database": "GeneCards",
"url": ""
},
{
"id": "P39060",
"database": "UniProt",
"url": ""
},
{
"id": "HMDBP13479",
"database": "HMDB Protein",
"url": ""
},
{
"id": "ENST00000355480",
"database": "Ensembl",
"url": ""
},
{
"id": "ENSP00000352798",
"database": "Ensembl",
"url": ""
},
{
"id": "NP_085059.2",
"database": "RefSeq",
"url": ""
},
{
"id": "P39060",
"database": "Pharos - Targets",
"url": ""
},
{
"id": "15766",
"database": "Orphanet",
"url": ""
},
{
"id": "ENST00000359759",
"database": "Ensembl",
"url": ""
},
{
"id": "ENSG00000182871",
"database": "OpenTargets",
"url": ""
},
{
"id": "ENSP00000347665",
"database": "Ensembl",
"url": ""
},
{
"id": "1BNL",
"database": "PDB",
"url": ""
}
]
},
{
"participant_id": "R-HSA-2225576",
"participant_name": "COL18A1(?-1571) [extracellular region]",
"crossref": [
{
"id": "ENSP00000498485",
"database": "Ensembl",
"url": ""
},
{
"id": "P39060",
"database": "PRO",
"url": ""
},
{
"id": "ENST00000651438",
"database": "Ensembl",
"url": ""
},
{
"id": "ENSG00000182871-COL18A1",
"database": "HPA",
"url": ""
},
{
"id": "NP_569711.2",
"database": "RefSeq",
"url": ""
},
{
"id": "3HSH",
"database": "PDB",
"url": ""
},
{
"id": "NP_569712.2",
"database": "RefSeq",
"url": ""
},
{
"id": "ENSG00000182871",
"database": "Ensembl",
"url": ""
},
{
"id": "3HON",
"database": "PDB",
"url": ""
},
{
"id": "P39060",
"database": "GeneCards",
"url": ""
},
{
"id": "15766",
"database": "Orphanet",
"url": ""
},
{
"id": "ENST00000355480",
"database": "Ensembl",
"url": ""
},
{
"id": "HMDBP13479",
"database": "HMDB Protein",
"url": ""
},
{
"id": "NP_085059.2",
"database": "RefSeq",
"url": ""
},
{
"id": "ENSP00000352798",
"database": "Ensembl",
"url": ""
},
{
"id": "P39060",
"database": "Pharos - Targets",
"url": ""
},
{
"id": "P39060",
"database": "UniProt",
"url": ""
},
{
"id": "ENST00000359759",
"database": "Ensembl",
"url": ""
},
{
"id": "ENSG00000182871",
"database": "OpenTargets",
"url": ""
},
{
"id": "1BNL",
"database": "PDB",
"url": ""
},
{
"id": "ENSP00000347665",
"database": "Ensembl",
"url": ""
}
]
},
{
"participant_id": "R-HSA-2470858",
"participant_name": "Cleaved collagen type XVIII multimer [extracellular region]",
"crossref": [
{
"id": "36080",
"database": "ChEBI",
"url": ""
}
]
},
{
"participant_id": "R-HSA-3827968",
"participant_name": "HSPG2(22-4196) [extracellular region]",
"crossref": [
{
"id": "16234",
"database": "Orphanet",
"url": ""
},
{
"id": "P98160",
"database": "Pharos - Targets",
"url": ""
},
{
"id": "ENSP00000363827",
"database": "Ensembl",
"url": ""
},
{
"id": "ENST00000374695",
"database": "Ensembl",
"url": ""
},
{
"id": "P98160",
"database": "PRO",
"url": ""
},
{
"id": "ENSG00000142798-HSPG2",
"database": "HPA",
"url": ""
},
{
"id": "3SH5",
"database": "PDB",
"url": ""
},
{
"id": "P98160",
"database": "UniProt",
"url": ""
},
{
"id": "HMDBP01713",
"database": "HMDB Protein",
"url": ""
},
{
"id": "ENSG00000142798",
"database": "Ensembl",
"url": ""
},
{
"id": "3SH4",
"database": "PDB",
"url": ""
},
{
"id": "P98160",
"database": "GeneCards",
"url": ""
},
{
"id": "NP_005520.4",
"database": "RefSeq",
"url": ""
},
{
"id": "NP_001278789.1",
"database": "RefSeq",
"url": ""
},
{
"id": "ENSG00000142798",
"database": "OpenTargets",
"url": ""
}
]
},
{
"participant_id": "R-HSA-3827980",
"participant_name": "HSPG2(4197-4391) [extracellular region]",
"crossref": [
{
"id": "ENSG00000142798-HSPG2",
"database": "HPA",
"url": ""
},
{
"id": "3SH5",
"database": "PDB",
"url": ""
},
{
"id": "P98160",
"database": "PRO",
"url": ""
},
{
"id": "ENST00000374695",
"database": "Ensembl",
"url": ""
},
{
"id": "16234",
"database": "Orphanet",
"url": ""
},
{
"id": "P98160",
"database": "Pharos - Targets",
"url": ""
},
{
"id": "ENSP00000363827",
"database": "Ensembl",
"url": ""
},
{
"id": "P98160",
"database": "GeneCards",
"url": ""
},
{
"id": "HMDBP01713",
"database": "HMDB Protein",
"url": ""
},
{
"id": "3SH4",
"database": "PDB",
"url": ""
},
{
"id": "ENSG00000142798",
"database": "Ensembl",
"url": ""
},
{
"id": "P98160",
"database": "UniProt",
"url": ""
},
{
"id": "NP_005520.4",
"database": "RefSeq",
"url": ""
},
{
"id": "ENSG00000142798",
"database": "OpenTargets",
"url": ""
},
{
"id": "NP_001278789.1",
"database": "RefSeq",
"url": ""
}
]
}
],
"reaction_enzymes": [
{
"uniprot_ac": "O43897",
"gene_name": "TLL1",
"activity": [
{
"ec_number": "3.4.24.-",
"activity": "",
"evidence": [
{
"id": "O43897",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/O43897"
}
]
}
]
},
{
"uniprot_ac": "O60882",
"gene_name": "MMP20",
"activity": [
{
"ec_number": "3.4.24.-",
"activity": "",
"evidence": [
{
"id": "O60882",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/O60882"
}
]
}
]
},
{
"uniprot_ac": "O60911",
"gene_name": "CTSV",
"activity": [
{
"ec_number": "3.4.22.43",
"activity": "The recombinant enzyme hydrolyzes proteins (serum albumin, collagen) and synthetic substrates (Z-Phe-Arg-NHMec > Z-Leu-Arg-NHMec > Z-Val-Arg-NHMec).",
"evidence": [
{
"id": "O60911",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/O60911"
}
]
},
{
"ec_number": "3.4.22.43",
"activity": "",
"evidence": [
{
"id": "O60911",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/O60911"
}
]
}
]
},
{
"uniprot_ac": "P07339",
"gene_name": "CTSD",
"activity": [
{
"ec_number": "3.4.23.5",
"activity": "Specificity similar to, but narrower than, that of pepsin A. Does not cleave the 4-Gln-|-His-5 bond in B chain of insulin.",
"evidence": [
{
"id": "P07339",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P07339"
}
]
},
{
"ec_number": "3.4.23.5",
"activity": "",
"evidence": [
{
"id": "P07339",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P07339"
}
]
}
]
},
{
"uniprot_ac": "P07711",
"gene_name": "CTSL",
"activity": [
{
"ec_number": "3.4.22.15",
"activity": "Specificity close to that of papain. As compared to cathepsin B, cathepsin L exhibits higher activity toward protein substrates, but has little activity on Z-Arg-Arg-NHMec, and no peptidyl-dipeptidase activity.",
"evidence": [
{
"id": "P07711",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P07711"
}
]
},
{
"ec_number": "3.4.22.15",
"activity": "",
"evidence": [
{
"id": "P07711",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P07711"
}
]
}
]
},
{
"uniprot_ac": "P07858",
"gene_name": "CTSB",
"activity": [
{
"ec_number": "3.4.22.1",
"activity": "Hydrolysis of proteins with broad specificity for peptide bonds. Preferentially cleaves -Arg-Arg-|-Xaa bonds in small molecule substrates (thus differing from cathepsin L). In addition to being an endopeptidase, shows peptidyl-dipeptidase activity, liberating C-terminal dipeptides.",
"evidence": [
{
"id": "P07858",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P07858"
}
]
},
{
"ec_number": "3.4.22.1",
"activity": "",
"evidence": [
{
"id": "P07858",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P07858"
}
]
}
]
},
{
"uniprot_ac": "P08254",
"gene_name": "MMP3",
"activity": [
{
"ec_number": "3.4.24.17",
"activity": "Preferential cleavage where P1', P2' and P3' are hydrophobic residues.",
"evidence": [
{
"id": "P08254",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P08254"
}
]
},
{
"ec_number": "3.4.24.17",
"activity": "",
"evidence": [
{
"id": "P08254",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P08254"
}
]
}
]
},
{
"uniprot_ac": "P09237",
"gene_name": "MMP7",
"activity": [
{
"ec_number": "3.4.24.23",
"activity": "Cleavage of 14-Ala-|-Leu-15 and 16-Tyr-|-Leu-17 in B chain of insulin. No action on collagen types I, II, IV, V. Cleaves gelatin chain alpha2(I) > alpha1(I).",
"evidence": [
{
"id": "P09237",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P09237"
}
]
},
{
"ec_number": "3.4.24.23",
"activity": "",
"evidence": [
{
"id": "P09237",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P09237"
}
]
}
]
},
{
"uniprot_ac": "P10619",
"gene_name": "CTSA",
"activity": [
{
"ec_number": "3.4.16.-",
"activity": "",
"evidence": [
{
"id": "P10619",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P10619"
}
]
},
{
"ec_number": "3.4.16.5",
"activity": "Release of a C-terminal amino acid with broad specificity.",
"evidence": [
{
"id": "P10619",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P10619"
}
]
},
{
"ec_number": "3.4.16.5",
"activity": "",
"evidence": [
{
"id": "P10619",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P10619"
}
]
}
]
},
{
"uniprot_ac": "P13497",
"gene_name": "BMP1",
"activity": [
{
"ec_number": "3.4.24.19",
"activity": "Cleavage of the C-terminal propeptide at Ala-|-Asp in type I and II procollagens and at Arg-|-Asp in type III.",
"evidence": [
{
"id": "P13497",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P13497"
}
]
},
{
"ec_number": "3.4.24.19",
"activity": "",
"evidence": [
{
"id": "P13497",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P13497"
}
]
},
{
"ec_number": "3.4.24.-",
"activity": "",
"evidence": [
{
"id": "P13497",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P13497"
}
]
}
]
},
{
"uniprot_ac": "P14091",
"gene_name": "CTSE",
"activity": [
{
"ec_number": "3.4.23.34",
"activity": "Similar to cathepsin D, but slightly broader specificity.",
"evidence": [
{
"id": "P14091",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P14091"
}
]
},
{
"ec_number": "3.4.23.34",
"activity": "",
"evidence": [
{
"id": "P14091",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P14091"
}
]
}
]
},
{
"uniprot_ac": "P14780",
"gene_name": "MMP9",
"activity": [
{
"ec_number": "3.4.24.35",
"activity": "Cleavage of gelatin types I and V and collagen types IV and V.",
"evidence": [
{
"id": "P14780",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P14780"
}
]
},
{
"ec_number": "3.4.24.35",
"activity": "",
"evidence": [
{
"id": "P14780",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P14780"
}
]
}
]
},
{
"uniprot_ac": "P25774",
"gene_name": "CTSS",
"activity": [
{
"ec_number": "3.4.22.27",
"activity": "Similar to cathepsin L, but with much less activity on Z-Phe-Arg-|-NHMec, and more activity on the Z-Val-Val-Arg-|-Xaa compound.",
"evidence": [
{
"id": "P25774",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P25774"
}
]
},
{
"ec_number": "3.4.22.27",
"activity": "",
"evidence": [
{
"id": "P25774",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P25774"
}
]
}
]
},
{
"uniprot_ac": "P39900",
"gene_name": "MMP12",
"activity": [
{
"ec_number": "3.4.24.65",
"activity": "Hydrolysis of soluble and insoluble elastin. Specific cleavages are also produced at 14-Ala-|-Leu-15 and 16-Tyr-|-Leu-17 in the B chain of insulin.",
"evidence": [
{
"id": "P39900",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P39900"
}
]
},
{
"ec_number": "3.4.24.65",
"activity": "",
"evidence": [
{
"id": "P39900",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P39900"
}
]
}
]
},
{
"uniprot_ac": "P43234",
"gene_name": "CTSO",
"activity": [
{
"ec_number": "3.4.22.42",
"activity": "The recombinant human enzyme hydrolyzes synthetic endopeptidase substrates including Z-Phe-Arg-NHMec and Z-Arg-Arg-NHMec.",
"evidence": [
{
"id": "P43234",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P43234"
}
]
},
{
"ec_number": "3.4.22.42",
"activity": "",
"evidence": [
{
"id": "P43234",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P43234"
}
]
}
]
},
{
"uniprot_ac": "P43235",
"gene_name": "CTSK",
"activity": [
{
"ec_number": "3.4.22.38",
"activity": "Broad proteolytic activity. With small-molecule substrates and inhibitors, the major determinant of specificity is P2, which is preferably Leu, Met > Phe, and not Arg.",
"evidence": [
{
"id": "P43235",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P43235"
}
]
},
{
"ec_number": "3.4.22.38",
"activity": "",
"evidence": [
{
"id": "P43235",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P43235"
}
]
}
]
},
{
"uniprot_ac": "P45452",
"gene_name": "MMP13",
"activity": [
{
"ec_number": "3.4.24.-",
"activity": "",
"evidence": [
{
"id": "P45452",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P45452"
}
]
}
]
},
{
"uniprot_ac": "P53634",
"gene_name": "CTSC",
"activity": [
{
"ec_number": "3.4.14.1",
"activity": "Release of an N-terminal dipeptide, Xaa-Yaa-|-Zaa-, except when Xaa is Arg or Lys, or Yaa or Zaa is Pro.",
"evidence": [
{
"id": "P53634",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P53634"
}
]
},
{
"ec_number": "3.4.14.1",
"activity": "",
"evidence": [
{
"id": "P53634",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/P53634"
}
]
}
]
},
{
"uniprot_ac": "Q99538",
"gene_name": "LGMN",
"activity": [
{
"ec_number": "3.4.22.34",
"activity": "Hydrolysis of proteins and small molecule substrates at -Asn-|-Xaa- bonds.",
"evidence": [
{
"id": "Q99538",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/Q99538"
}
]
},
{
"ec_number": "3.4.22.34",
"activity": "",
"evidence": [
{
"id": "Q99538",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/Q99538"
}
]
}
]
},
{
"uniprot_ac": "Q9BYF1",
"gene_name": "ACE2",
"activity": [
{
"ec_number": "3.4.-.-",
"activity": "",
"evidence": [
{
"id": "Q9BYF1",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/Q9BYF1"
}
]
},
{
"ec_number": "3.4.17.23",
"activity": "angiotensin II + H2O = angiotensin-(1-7) + L-phenylalanine.",
"evidence": [
{
"id": "Q9BYF1",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/Q9BYF1"
}
]
},
{
"ec_number": "3.4.17.-",
"activity": "",
"evidence": [
{
"id": "Q9BYF1",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/Q9BYF1"
}
]
},
{
"ec_number": "3.4.17.23",
"activity": "",
"evidence": [
{
"id": "Q9BYF1",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/Q9BYF1"
}
]
}
]
},
{
"uniprot_ac": "Q9UBX1",
"gene_name": "CTSF",
"activity": [
{
"ec_number": "3.4.22.41",
"activity": "The recombinant enzyme cleaves synthetic substrates with Phe and Leu (better than Val) in P2, with high specificity constant (kcat/Km) comparable to that of cathepsin L.",
"evidence": [
{
"id": "Q9UBX1",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/Q9UBX1"
}
]
},
{
"ec_number": "3.4.22.41",
"activity": "",
"evidence": [
{
"id": "Q9UBX1",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/Q9UBX1"
}
]
}
]
},
{
"uniprot_ac": "Q9Y6L7",
"gene_name": "TLL2",
"activity": [
{
"ec_number": "3.4.24.-",
"activity": "",
"evidence": [
{
"id": "Q9Y6L7",
"database": "UniProtKB",
"url": "https://www.uniprot.org/uniprot/Q9Y6L7"
}
]
}
]
}
],
"biomarkers": [],
"synthesized_glycans": [],
"cluster_types": [
{
"name": "isoformset.uniprotkb",
"label": "Isoforms"
},
{
"name": "homologset.mgi",
"label": "MGI Homologs"
},
{
"name": "homologset.oma",
"label": "OMA Homologs"
}
],
"sequence_features": {
"n_linked_sites": [
175,
221
],
"o_linked_sites": [
218,
223
],
"snv_sites": [
3,
177,
218,
223
],
"glycation_sites": [],
"phosphorylation_sites": [],
"sequon_annotation_sites": [
{
"start_pos": 221,
"end_pos": 223
}
]
},
"section_stats": [
{
"table_id": "glycosylation",
"table_stats": [
{
"field": "total",
"count": 17
},
{
"field": "total_sites",
"count": 4
},
{
"field": "n_linked_glycans",
"count": 13
},
{
"field": "n_linked_glycan_sites",
"count": 3
},
{
"field": "o_linked_glycans",
"count": 1
},
{
"field": "o_linked_glycan_sites",
"count": 2
}
],
"sort_fields": [
"glytoucan_ac",
"type",
"subtype",
"site_category",
"site_seq",
"relation",
"comment",
"start_pos",
"start_aa",
"end_pos",
"end_aa",
"residue",
"site_lbl"
]
},
{
"table_id": "glycosylation_reported",
"table_stats": [
{
"field": "total",
"count": 1
},
{
"field": "total_sites",
"count": 1
},
{
"field": "n_linked_glycans",
"count": 0
},
{
"field": "n_linked_glycan_sites",
"count": 1
},
{
"field": "o_linked_glycans",
"count": 0
},
{
"field": "o_linked_glycan_sites",
"count": 0
}
],
"sort_fields": [
"glytoucan_ac",
"type",
"subtype",
"site_category",
"site_seq",
"relation",
"comment",
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